Activation of perforant path neurons to field CA1 by hippocampal projections

Previous evidence showed that single-shock stimulation of dorsal hippocampal commissure (PSD) fibers to the entorhinal cortex led to sequential activation of perforant path neurons to the dentate gyrus, dentate granule cells, pyramidal neurons of hippocampal fields CA3 and CA1, and, through reentrant hippocampal impulses, neurons of deep and superficial layers of the entorhinal cortex. The aim of the present study was to ascertain whether perforant path neurons to CA1 are activated by the PSD input and/or by the reentrant hippocampal impulses in this model. Field potentials evoked by single-shock (0.1-Hz) or repetitive (1-4 Hz) PSD stimulation were recorded in anesthetized guinea pigs from the entorhinal cortex, dentate gyrus, fields CA1 and CA3, and subiculum. A current source-density analysis of the evoked potentials was used to localize the input to field CA1 and dentate gyrus. After either single-shock or repetitive PSD stimulation, an early current sink was found in the molecular layer of the dentate gyrus, but no sink was present in CA1. With low-frequency PSD stimulation, a late (approximately 40-ms) surface positive wave occurred in field CA1 alone. During this wave, a current sink was found in the stratum lacunosum-moleculare of CA1, but no sink was present in the dentate gyrus. The late wave had threshold and magnitude related to the building up of the response evoked by reentrant hippocampal impulses in layer III of the entorhinal cortex and was abolished by selective interruption of the perforant path to CA1. The results show that the commissural input to the entorhinal cortex activates perforant path neurons to the dentate gyrus, but not those to field CA1 which are recruited by repetitive hippocampal impulses. These findings show different frequency-dependent patterns of loop operation that might be related to different behaviors.     

Behavior-dependent evoked potentials in the hippocampal CA1 region of the rat. I. Correlation with behavior and egg

As an alternative approach to the study of hippocampal function in relation to behavior, the averaged evoked potentials (AEPs) evoked by electrical stimulation of the Schaffer collaterals (SCH), the alveus and the contralateral hippocampus were recorded at various depths in the hippocampal CA1 region of freely moving rats with chronically implanted electrodes.Significant correlations between AEPs, behavior and EEG were found. At one end of the continuum of AEPs were those recorded during large irregular activity (LIA), an EEG pattern associated with slow-wave sleep or awake-immobility. These AEPs had a large early peak and low-amplitude late peaks. At the other end of the continuum, during high frequency theta EEG associated with behaviors such as walking, postural change or phasic paradoxical sleep, AEPs had a smaller early peak, increased later peak(s) and appeared oscillatory. The evoked population spike, a synchronous postsynaptic firing of CA1 neurons, was smaller during behaviors associated with theta than during those associated with LIA.It is postulated that a recurrent inhibitory circuit within the hippocampus can account for the change of the AEPs with EEG and behavior and with stimulus intensity. During theta EEG, the negative feedback may increase such that the evoked population excitatory postsynaptic potential and the evoked population spike decrease and oscillatory response is more readily elicited. The excitability state of hippocampal CA1 may be described by the negative feedback gain in this model.     

Input-output relations in the entorhinal-hippocampal-entorhinal loop: Entorhinal cortex and dentate gyrus

The pattern of impulse transfer along the entorhinal-hippocampal-entorhinal loop has been analyzed in the guinea pig by field potential analysis. The loop was driven by impulse volleys conducted by presubicular commissural fibers, directly stimulated in the dorsal psalterium, which monosynaptically activated perforant path neurons in the medial entorhinal cortex. Perforant path volleys activated in sequence the dentate gyrus, field CA3, field CA1, subiculum, and entorhinal cortex. Input-output curves were reconstructed from responses simultaneously recorded from different stations along the loop. The entorhinal response to the presubicular volley was found to increase gradually with respect to its input. The population excitatory postsynaptic potential (EPSP) of the dentate gyrus granule cells had a similar behavior. By contrast, the input-output relation between the granule cell population spike and population EPSP was described by a very steep sigmoid curve. The population spike of CA3 and CA1 pyramidal neurons as well as the response evoked in the entorhinal cortex by the hippocampal output had slightly higher threshold than the granule cell population spike and, like the latter, abruptly reached maximum amplitude. These findings show that the entorhinal-hippocampal-entorhinal loop transforms a linear input in a non-linear, almost all-or-none output and that the dentate gyrus is the critical site where the transformation occurs. Beyond the dentate gyrus, the loop appears very permeant to impulse traffic. © 1995 Wiley-Liss, Inc.     

Evoked field responses, recurrent inhibition, long-term potentiation and immobility-related nonrhythmical EEG in the dentate gyrus of fimbria-fornix-lesioned and control rats.

The effects of complete fimbria-fornix (FF) lesioning, bilateral medial-FF lesioning and systemic administration of a novel noradrenergic alpha 2-antagonist, atipamezole, on electrophysiological properties of the hippocampal formation were studied in the rat. In the hilus of the dentate gyrus (DG) complete FF lesioning abolished the long-term potentiation (LTP) of the population spike (PS), which in control rats could be induced by the application of high-frequency stimulus trains on the medial perforant pathway (PP). Several other electrophysiological properties examined in the medial-FF-lesioned rats changed as well. These changes included a decrease in the efficacy of recurrent inhibition and slight differences in granular cell population response evoked by perforant path stimulation. Also, in the DG the power of awake immobility-related nonrhythmical electroencephalogram (EEG) was significantly lower in FF-lesioned rats than in controls. In the DG of control rats systemic administration of atipamezole (1 mg/kg) shifted the population spike-field postsynaptic potential response curve towards the left. In FF-lesioned rats this drug had no effects. The slight effects of atipamezole would be in line with earlier studies, which have shown that noradrenergic activation facilitates neuronal transmission in the DG. Possible explanations for the changes seen in FF-lesioned rats include deafferentation of different subcortical projections and increased epileptic activity. These established changes in synaptic plasticity, recurrent inhibition, nonrhythmical EEG and evoked responses would indicate that information processing is severely hampered in the first stage of the hippocampal trisynaptic circuit after fimbria-fornix lesioning. Thus, the results show that aminergic/cholinergic projections have a significant role in information processing in the dentate gyrus of hippocampal formation.     

Hippocampal responses evoked by tooth pulp and acoustic stimulation: Depth profiles and effect of behavior

Averaged evoked potentials and unitary discharges in response to tooth pulp and acoustic click stimuli were recorded from the hippocampus of freely moving rats. The spatial distribution of evoked field responses to tooth pulp stimulation and acoustic clicks were identical. Averaged evoked potentials consisted of a large negative deflection (N1) preceded by a small positive potential (P1). The shortest latency N1 in response to tooth pulp stimulation was recorded from the middle third of the dentate molecular layer and the outer portion of apical dendrites of CA3 (27 ms). The peak latency of N1 was significantly longer (34 ms) in the stratum radiatum of CA1. Laminar profiles of N1 in the dentate gyrus and CA3 were similar to that evoked by electrical stimulation of the medial entorhinal afferents; in CA1 the depth profiles of the potentials were similar to the response profile evoked by the Schaffer collaterals. Largest amplitude P1 was obtained from above the pyramidal layer of CA1 and the hilus. Both sensory modalities were able to modify the discharge rate of neurons in all hippocampal regions. The amplitude of evoked field potentials and cellular responses were dependent upon both the ongoing behavior of the animal and the nature of its response to the stimulus. The largest amplitude evoked potentials were recorded during immobility and slow wave sleep. On the other hand, virtually no potentials were obtained during exploratory behaviors associated with theta EEG activity. The findings indicate that information about sensory stimuli can reach the hippocampus by two distinctive pathways: a short latency inhibitory input via the fimbria-fornix and a longer latency path via the entorhinal cortex. It is suggested that neuronal mechanisms involved in theta EEG block the sequential activation of the unidirectional entorhinal-hippocampal circuitry.     

Feedforward and feedback inhibition of hippocampal principal cell activity evoked by perforant path stimulation: GABA-mediated mechanisms that regulate excitability in vivo.

Hippocampal field potentials evoked by paired-pulse perforant path stimulation were used to identify normal feedforward and feedback inhibitory influences on hippocampal principal cells. Three distinct aspects of inhibitory function were identified in the dentate gyrus. They are: (1) first spike amplitude-dependent inhibition of the second spike, which at low stimulus frequency is primarily feedback in nature; (2) frequency-dependent inhibition of a single spike or the first spike of a pair, which occurs as stimulus frequency is increased from 0.1 to 1.0 Hz and which is primarily a reflection of feedforward inhibition; and (3) frequency-dependent inhibition of the second spike that is relatively independent of first spike amplitude and probably due to a combination of feedforward and feedback mechanisms. The results indicate that granule cell recurrent inhibition alone, evoked at low stimulus frequency, is relatively brief and weak. At higher frequencies, probably more relevant to physiological activity, feedforward inhibitory activity is recruited. The combination of feedforward and feedback mechanisms results in strong, maximal duration, granule cell inhibition. Similar frequency dependence of inhibition was not seen in area CA1 in response to ipsilateral perforant path stimulation since low frequency stimulation did not evoke CA1 spikes. CA3 stimulation did evoke large contralateral CA1 population spikes, but paired-pulse inhibition was weaker than that evoked by ipsilateral perforant path stimulation in terms of the duration of inhibition and the ability to suppress the development of epileptiform behavior. The identification of simple tests that reflect distinct inhibitory processes in vivo permits similar studies to be conducted in vitro to determine how to preserve inhibitory processes for cellular studies of normal and human epileptic tissue in which the state of excitatory--inhibitory balance is the subject. These results also form the basis for the interpretation of the following study (Sloviter, 1991), which addresses the relationship between selective dentate interneuron loss and the pathophysiology that accompanies it.     

Cysteamine potentiates entorhinal activation of dentate gyrus granule cells in rats

A dense plexus of somatostatin-positive fibers and varicosities is observed in the outer two-thirds of the dentate gyrus molecular layer where the glutamatergic perforant path afferents from the entorhinal cortex terminate. To test for a functional interaction between these two pathways, we examined the effects of Cysteamine, which enhances somatostatin release for a few hours after administration but produces subsequent depletion of somatostatin lasting several days, on perforant path evoked potentials recorded in the dentate gyrus. Cysteamine (50–400 mg/kg, IP) increased the population spike dose-dependently both in anesthetized and in awake rats, but the slope of the population excitatory postsynaptic potential (EPSP) was left unchanged or even decreased. The antidromic population spike evoked by mossy fiber stimulation was not changed by cysteamine. The change is thought to be due to the increase in slope of the EPSP-spike relationship. In the hippocampal slice preparation, a similar effect of the drug (1–5 mM) on dentate evoked potentials was observed, suggesting that cysteamine acts through its effects on somatostatin in the hippocampus itself. In chronically implanted awake animals, the perforant path population spike was increased 1 h after cysteamine but returned to the predrug level by 24 h when somatostatin seemed to be depleted. These results suggest that hippocampal somatostatin released by cysteamine potentiates the response of dentate granule cells to perforant path input, without directly affecting synaptic transmission or general cell excitability.     

Parallel activation of field CA2 and dentate gyrus by synaptically elicited perforant path volleys

Previous studies showed that dorsal psalterium (PSD) volleys to the entorhinal cortex (ENT) activated in layer II perforant path neurons projecting to the dentate gyrus. The discharge of layer II neurons was followed by the sequential activation of the dentate gyrus (DG), field CA3, field CA1. The aim of the present study was to ascertain whether in this experimental model field, CA2, a largely ignored sector, is activated either directly by perforant path volleys and/or indirectly by recurrent hippocampal projections. Field potentials evoked by single-shock PSD stimulation were recorded in anesthetized guinea pigs from ENT, DG, fields CA2, CA1, and CA3. Current source-density (CSD) analysis was used to localize the input/s to field CA2. The results showed the presence in field CA2 of an early population spike superimposed on a slow wave (early response) and of a late and smaller population spike, superimposed on a slow wave (late response). CSD analysis during the early CA2 response showed a current sink in stratum lacunosum-moleculare, followed by a sink moving from stratum radiatum to stratum pyramidale, suggesting that this response represented the activation and discharge of CA2 pyramidal neurons, mediated by perforant path fibers to this field. CSD analysis during the late response showed a current sink in middle stratum radiatum of CA2 followed by a sink moving from inner stratum radiatum to stratum pyramidale, suggesting that this response was mediated by Schaffer collaterals from field CA3. No early population spike was evoked in CA3. However, an early current sink of small magnitude was evoked in stratum lacunosum-moleculare of CA3, suggesting the presence of synaptic currents mediated by perforant path fibers to this field. The results provide novel information about the perforant path system, by showing that dorsal psalterium volleys to the entorhinal cortex activate perforant path neurons that evoke the parallel discharge of granule cells and CA2 pyramidal neurons and depolarization, but no discharge of CA3 pyramidal neurons. Consequently, field CA2 may mediate the direct transfer of ENT signals to hippocampal and extrahippocampal structures in parallel with the DG-CA3-CA1 system and may provide a security factor in situations in which the latter is disrupted.     

Hippocampal kindling induced paired-pulse depression in the dentate gyrus and paired-pulse facilitation in CA3

Rats received high frequency (100 Hz, 1 s) hippocampal stimulations that evoked afterdischarges (ADs) in a partial kindling model of epilepsy. Kindled rats were given 15 ADs over 3 days. Control rats received the same stimulation pulses at 0.17 Hz (low frequency stimulation, LFSs). Subsequent to in vivo stimulations, hippocampal slices were obtained from the rats and extracellular field responses were recorded in the CA3 cell layer following CA1 stratum radiatum stimulation, and in the granule cell layer of the dentate gyrus (DG) following perforant path stimulation. At the DG, the paired-pulse facilitation of the population spike was depressed in the kindled than the control group, on 1 day or 23 days post ADs/LFSs. The excitatory postsynaptic potential (EPSP) responses in DG following single or paired pulses were not different between kindled and control slices. At CA3, paired-pulse facilitation of both the population spike and the population EPSP was increased in the kindled compared to the control group.     

Lonf-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity

In urethane-anesthetized rats, high frequency stimulation was applied to the medial perforant pathway at various time intervals (50, 100, 200, 350 and 500 ms) following stimulation of the same pathway by a single pulase of equal intensity. Recordings of dentate gyrus granule cell evoked responses were made to investigate the range of stimuli that are effective in inducing long-term potentiation (LTP). LTP was induced almost exclusively at the 200 ms interval, corresponding to the periodicity if the theta rhythm. Taken in conjunction with similar findings reported in the CA1 field of the hippocampal slice, these results suggest that the correlation between theta rhythm periodicity and LTP is a general phenomenon within the hippocampal formation and lends further support to the hypothesis that the naturally occuring theta rhythm may play a modulatory role in the induction of LTP.     

Long-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity

In urethane-anesthetized rats, high frequency stimulation was applied to the medial perforant pathway at various time intervals (50, 100, 200, 350 and 500 ms) following stimulation of the same pathway by a single pulse of equal intensity. Recordings of dentate gyrus granule cell evoked responses were made to investigate the range of stimuli that are effective in inducing long-term potentiation (LTP). LTP was induced almost exclusively at the 200 ms interval, corresponding to the periodicity of the theta rhythm. Taken in conjunction with similar findings reported in the CA1 field of the hippocampal slice, these results suggest that the correlation between theta rhythm periodicity and LTP is a general phenomenon within the hippocampal formation and lends further support to the hypothesis that the naturally occurring theta rhythm may play a modulatory role in the induction of LTP.     

Spatial distribution of hippocampal responses to dental pulp stimulation and acoustic clicks

Evoked potentials and unitary discharges in responses to tooth pulp and acoustic click stimuli were recorded from the hippocampus of freely moving rats. The spatial distribution of evoked field responses to tooth pulp stimulation and acoustic clicks were identical. Averaged evoked potentials consisted of a large negative deflection (N1) preceded by a small positive potential (P1). The shortest latency N1 was recorded from the middle third of the dentate molecular layer and the outer portion of apical dendrites of Ca3 (27 ms). The peak latency of N1 was significantly longer (34 ms) in the stratum radiatum of CA1. Laminar profiles of N1 in the dentate gyrus and CA3 were similar to that evoked by electrical stimulation of the perforant path and in CA1 similar to the response profile evoked by the Schaffer collaterals. The largest amplitude P1 was observed above the pyramidal layer of CA1 and the hilus. Both sensory modalities were able to modify the discharge rate of neurons in all hippocampal regions. A conclusion is made that information about sensory stimuli can reach the hippocampus by two distinctive pathways: a short-latency inhibitory input via the fimbrial fornix and a longer-latency path via the entorhinal cortex.     

Glutamatergic activation of the medial septum complex: an enhancement of the dentate gyrus population spike and accompanying EEG and unit changes

A large number of cells from the medial septum complex (MSC) innervate the dentate gyrus of the hippocampus. Electrical prestimulation of the MSC enhances perforant path-dentate gyrus evoked field potentials. Considering the large number of fibres that pass through this region, the effects glutamatergic stimulation of the MSC had on dentate gyrus field potentials, and accompanying changes in units, and EEG, was investigated in urethane-anaesthetized rats. The perforant path was stimulated at a rate of 0.1 Hz, evoking an EPSP and a population spike recorded in the dentate gyrus granule cell layer. L-glutamate was delivered by pressure ejection. Glutamate ejection to the MSC produced a significant enhancement of the population spike. The duration of enhancement ranged from 1 to 49 min ( approximately =10.5 min). A consistent, but relatively short increase in the EPSP slope was also demonstrated. MSC activation induced a theta rhythm in 7 of 10 animals (duration=20-112 s). Theta rhythm induction preceded spike enhancement and occurred for a shorter duration than the enhancement. The effects on spontaneous unit activity were mixed. However, all changes in firing rate preceded spike enhancement, and their duration rarely coincided with the duration of the spike enhancement. The population spike enhancement usually occurred without evidence of a change in paired-pulse inhibition.     

Changes in neuronal transmission in the rat hippocampus during behavior

Rats with implanted stimulating and recording microelectrodes were trained in a straight alley to repeatedly press a bar placed at one end of the alley and to run for water reward available at the other end. Stimulating the commissural input evoked field EPSP and population spike in the CA1 region while no population spike was observed in the dentate area. The amplitude of the CA1 population spike was maximum during running and smallest during drinking. Field potentials in the dentate gyrus changed in an opposite manner (drink>groom>press>run). Perforant path evoked cell discharges in the dentate gyrus which were maximal during drinking and smallest during running. The behavior dependent changes of the evoked potentials covaried with the frequency and power of the simultaneously recorded theta activity. Perforant path stimulation during the negative-going phase of the dentate theta cycle evoked significantly greater granule cell responses than stimuli during the positive-going phase. These observations suggest that the medial septum exerts a potent biasing effect on the efficacy of other afferents to the hippocampus.     

Acetylcholine modulates averaged sensory evoked responses and perforant path evoked field potentials in the rat dentate gyrus

The effect of localized application of acetylcholine (ACh) on well characterized components of sensory evoked and electrically induced potentials in the dentate gyrus was investigated in rats while performing a tone discrimination task. Local pressure application of ACh to the granule cell layer of the dentate gyrus through the recording pipette increased the amplitude of perforant path evoked population spikes without changing the amplitude of the field EPSP. When the pipette was relocated to the outer molecular layer of the dentate gyrus (OM), ACh application decreased the amplitude of the perforant path field EPSP. Two major components of the averaged auditory evoked potential (AEP) recorded during criterion performance of the discrimination task were significantly changed by dendritic application of ACh. The N1 component of the OM AEP which has been shown to reflect perforant path synaptic activity decreased in amplitude while the N2 component which represents activity from septal connections, was significantly increased. These effects were not due to the pressure ejection procedure nor drug related changes in behavioral performance of the task. The results suggest that ACh may act to differentially modulate the synaptic excitability of dentate granule cells, allowing them to acquire responses to sensory stimulation during the establishment and maintenance of discrimination learning.     

Changes of neuronal transmission in the hippocampus after transient ischemia in spontaneously hypertensive rats and the protective effects of MK-801.

BACKGROUND AND PURPOSE: I studied the mechanism of postischemic neuronal degeneration in the hippocampus by an electrophysiological method. METHODS: Sequential changes of field potentials evoked by perforant path stimulation in the dentate gyrus and the CA1 region of the hippocampus were evaluated in spontaneously hypertensive rats up to 7 days after transient global ischemia induced by bilateral occlusion of the carotid arteries for 20 minutes after electrocauterization of the vertebral arteries. Animals were treated with vehicle or the excitotoxin antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10 amine (MK-801, 2 mg/kg or 5 mg/kg) intraperitoneally 30 minutes before ischemia. RESULTS: Complete recovery of the population spike was observed in the dentate gyrus within 24 hours after recirculation, followed by a gradual reduction of population spike amplitude. In contrast, population spike in the CA1 region showed partial recovery 24 hours after recirculation, and an abrupt reduction of population spike amplitude occurred on day 2. There was no significant enhancement of population spike amplitude in either region throughout the experiment. Interneuronal recurrent inhibition in the dentate gyrus was enhanced on day 4, and ischemic changes were apparent in the CA1 pyramidal cells on day 7. Pretreatment with 5 mg/kg MK-801 prevented field potential and pathological changes completely in the dentate gyrus and partially in the CA1 region. CONCLUSIONS: My results indicate that pathological changes of the CA1 pyramidal neurons after transient ischemia may not be the result of postischemic overstimulation. However, neuronal transmission in the CA1 region may be persistently impaired during or after transient ischemia.     

“Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies

Sustained electrical stimulation of the perforant path in urethane-anesthetized rats evoked hippocampal granule cell population spikes and epileptiform discharges. After stimulation, recurrent inhibition in the granule cell layer was abolished. Light microscopic analysis revealed a highly reproducible pattern of hippocampal damage to dentate pyramidal basket cells, hilar cells in general and CA3 and CA1 pyramidal cells. CA2 pyramidal cells and dentate granule cells were relatively unaffected. When perforant path stimulation on one side of the brain evoked bilateral granule cell discharges, damage was bilateral. Unilateral hippocampal seizures were associated with unilateral hippocampal damage. Rapid Golgi-stained hippocampi exhibited spherical dendritic swellings at the sites of termination of excitatory entorhinal afferents to the hippocampus and in the mossy fiber region. Electrical stimulation of a single excitatory afferent to the hippocampus appears to reproduce the “epileptic” pattern of hippocampal damage without using convulsant drugs and without causing motor convulsions. It is suggested that seizure-associated brain damage in caused by excessive pre-synaptic release of excitatory transmitter that induces intracellular post-synaptic changes that lead to dendritic swelling and cell death.     

Carbachol-induced EEG 'theta' in hippocampal formation slices: evidence for a third generator of theta in CA3c area

The topography of carbachol-induced EEG theta activity was studied using the hippocampal formation slice preparation. Systematic tracking with electrodes exhibited two amplitude maxima of cholinergic-induced theta, one located in the stratum oriens of the CA1 pyramidal cells and the other in a region of CA3c pyramidal neurons. In addition, mapping experiments demonstrated EEG theta in the CA3a and CA3b cell body layers, but not in the subicular and parasubicular regions, or the ventral blade of the dentate gyrus. Furthermore, transected slice (trans-slice) preparations used in the present study revealed that the CA3c region could generate carbachol-induced theta independently of CA1 and dentate gyrus generator zones and conversely, CA1 and dentate gyrus areas were capable of generating cholinergic-induced theta rhythm independently of the CA3c region. These results provide strong evidence for 3 independent, anatomically separated generators of theta: one located in the stratum oriens of CA1 neurons, a second in the stratum moleculare of the dentate gyrus and a third one in the region of Ca3c cells. In addition, the results support previous in vivo suggestions that theta rhythm can be either elicited or blocked by cholinergic agents acting on sites within the hippocampal formation.     

Characteristics of CA1 activation through the hippocampal trisynaptic pathway in the unanaesthetized rat

The hippocampal CA1 field is activated by the entorhinal cortex mainly through the hippocampal excitatory trisynaptic circuit. Field responses of the CA1 region were evoked by ipsilateral CA3 or perforant path volley (mono- or trisynaptic activation, respectively) in paralyzed, locally anaesthetized rats and studied as a function of the stimulus patterns presented. The relationship of these responses with the concomitant EEG was also explored. Results showed that mono- and especially trisynaptically evoked responses were progressively enhanced by increasing the stimulus frequency from 0.1 to 1.0 Hz. At specific intensities the trisynaptically evoked population spike (PS) was present only with a rather fixed frequency of stimulation (approximately 0.5 Hz). PS was produced in 100% of the responses using 0.7 Hz, indicating the existence of a threshold-like level for this stimulus parameter. The frequency of presented paired pulses differentially affected pair-pulse facilitation of mono- and trisynaptically evoked excitatory postsynaptic potentials (EPSP): higher frequency decreased the former and increased the latter. All evoked responses studied (i.e. EPSP and PS) showed steep increments and decrements in amplitude, clearly developing several clusters. Moreover, the amplitude distribution of trisynaptic PS often varied spontaneously from maximal to negligible values, showing an all-or-none distribution. Clustering was interpreted as evidence of the existence in the hippocampus of functional neuronal aggregates. All-or-none distribution of trisynaptic PS was found to be associated with the EEG pattern, PS amplitude being maximal during irregular EEG activity and minimal during theta rhythm. Present results suggest that (1) the entorhinal cortex may exert modulatory actions on CA1 by a mechanism widely based on the frequency of the input; (2) information transfer from the entorhinal cortex to other brain areas throughout the hippocampus is biased by hippocampal EEG; and (3) electronic coupling may be functionally predominant in the hippocampus.     

Modulation of hippocampal excitability and seizures by galanin.

Previous studies have shown that the expression of the neuropeptide galanin in the hippocampus is altered by seizures and that exogenous administration of galanin into the hippocampus attenuates seizure severity. To address the role of endogenous galanin in modulation of hippocampal excitability and its possible role in seizure mechanisms, we studied two types of transgenic mice: mice with a targeted disruption of the galanin gene (GalKO) and mice that overexpress the galanin gene under a dopamine-beta-hydroxylase promoter (GalOE). GalKO mice showed increased propensity to develop status epilepticus after perforant path stimulation or systemic kainic acid, as well as greater severity of pentylenetetrazol-induced convulsions. By contrast, GalOE mice had increased resistance to seizure induction in all three models. Physiological tests of hippocampal excitability revealed enhanced perforant path-dentate gyrus long-term potentiation (LTP) in GalKO and reduced LTP in GalOE. GalKO showed increased duration of afterdischarge (AD) evoked from the dentate gyrus by perforant path simulation, whereas GalOE had increased threshold for AD induction. Depolarization-induced glutamate release from hippocampal slices was greater in GalKO and lower in GalOE, suggesting that alterations of physiological and seizure responses in galanin transgenic animals may be mediated through modulation of glutamate release. Our data provide further evidence that hippocampal galanin acts as an endogenous anticonvulsant and suggest that genetically induced changes in galanin expression modulate both hippocampal excitability and predisposition to epileptic seizures.